title: Histone methylation at H3K9: evidence for a restrictive epigenome in schizophrenia.
abstract: OBJECTIVE
  Epigenetic changes are stable and long-lasting chromatin modifications that regulate genomewide and local gene activity. The addition of two methyl groups to the 9th lysine of histone 3 (H3K9me2) by histone methyltransferases (HMT) leads to a restrictive chromatin state, and thus reduced levels of gene transcription. Given the numerous reports of transcriptional down-regulation of candidate genes in schizophrenia, we tested the hypothesis that this illness can be characterized by a restrictive epigenome.
  
  
  METHODS
  We obtained parietal cortical samples from the Stanley Foundation Neuropathology Consortium and lymphocyte samples from the University of Illinois at Chicago (UIC). In both tissues we measured mRNA expression of HMTs GLP, SETDB1 and G9a via real-time RT-PCR and H3K9me2 levels via western blot. Clinical rating scales were obtained from the UIC cohort.
  
  
  RESULTS
  A diagnosis of schizophrenia is a significant predictor for increased GLP, SETDB1 mRNA expression and H3K9me2 levels in both postmortem brain and lymphocyte samples. G9a mRNA is significantly increased in the UIC lymphocyte samples as well. Increased HMT mRNA expression is associated with worsening of specific symptoms, longer durations of illness and a family history of schizophrenia.
  
  
  CONCLUSIONS
  These data support the hypothesis of a restrictive epigenome in schizophrenia, and may associate with symptoms that are notoriously treatment resistant. The histone methyltransferases measured here are potential future therapeutic targets for small molecule pharmacology, and better patient prognosis.
authors.affiliation: The Psychiatric Institute, University of Illinois at Chicago, 1601 W. Taylor St., Chicago, IL 60612, United States.
authors.forename: Kayla A
authors.initials: KA
authors.lastname: Chase
authors.forename: David P
authors.initials: DP
authors.lastname: Gavin
authors.forename: Alessandro
authors.initials: A
authors.lastname: Guidotti
authors.forename: Rajiv P
authors.initials: RP
authors.lastname: Sharma
mesh_terms: D000328:Adult; D002540:Cerebral Cortex / Q000378:metabolism / Q000473:pathology; D057890:Epigenomics; D005260:Female; D005786:Gene Expression Regulation / Q000502:physiology*; D011495:Histone-Lysine N-Methyltransferase / Q000235:genetics / Q000378:metabolism*; D006657:Histones / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D016014:Linear Models; D008214:Lymphocytes / Q000378:metabolism / Q000473:pathology; D008239:Lysine / Q000235:genetics; D008297:Male; D008745:Methylation; D008875:Middle Aged; D011180:Postmortem Changes; D011496:Protein Methyltransferases / Q000235:genetics / Q000378:metabolism; D011569:Psychiatric Status Rating Scales; D012333:RNA, Messenger / Q000378:metabolism; D012559:Schizophrenia / Q000235:genetics* / Q000473:pathology
chemical_list: D006657:Histones; D012333:RNA, Messenger; C455847:EHMT1 protein, human; D011496:Protein Methyltransferases; D011495:Histone-Lysine N-Methyltransferase; C454062:SETDB1 protein, human; D008239:Lysine
keywords: Chromatin; Epigenetics; Histone methylation; Lymphocyte; Postmortem Brain; Schizophrenia